Cristina Carrera

Dermoscopy Improves Accuracy of Primary Care Physicians to Triage Lesions Suggestive of Skin Cancer

PURPOSE Primary care physicians (PCPs) constitute an appropriate target for new interventions and educational campaigns designed to increase skin cancer screening and prevention. The aim of this randomized study was to determine whether the adjunct of dermoscopy to the standard clinical examination improves the accuracy of PCPs to triage lesions suggestive of skin cancer. PATIENTS AND METHODS PCPs in Barcelona, Spain, and Naples, Italy, were given a 1-day training course in skin cancer detection and dermoscopic evaluation, and were randomly assigned to the dermoscopy evaluation arm or naked-eye evaluation arm. During a 16-month period, 73 physicians evaluated 2,522 patients with skin lesions who attended their clinics and scored individual lesions as benign or suggestive of skin cancer. All patients were re-evaluated by expert dermatologists at clinics for pigmented lesions. Referral accuracy of both PCP groups was calculated by their scores, which were compared to those tabulated for dermatologists. RESULTS Referral sensitivity, specificity, and positive and negative predictive values were 54.1%, 71.3%, 11.3%, and 95.8%, respectively, in the naked-eye arm, and 79.2%, 71.8%, 16.1%, and 98.1%, respectively, in the dermoscopy arm. Significant differences were found in terms of sensitivity and negative predictive value (P = .002 and P = .004, respectively). Histopathologic examination of equivocal lesions revealed 23 malignant skin tumors missed by PCPs performing naked-eye observation and only six by PCPs using dermoscopy (P = .002). CONCLUSION The use of dermoscopy improves the ability of PCPs to triage lesions suggestive of skin cancer without increasing the number of unnecessary expert consultations.

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

In Vivo Confocal Microscopic and Histopathologic Correlations of Dermoscopic Features in 202 Melanocytic Lesions

OBJECTIVES To identify in vivo microscopic substrates of the dermoscopic patterns of melanocytic lesions and to correlate them with histopathologic features. DESIGN Before excision, lesion areas that showed characteristic dermoscopic patterns were imaged by dermoscopy and confocal microscopy and directly correlated with histopathologic features. SETTING Departments of Dermatology of the University of Modena and Reggio Emilia and Hospital Clínico of Barcelona, between July 2006 and March 2007. Patients Patients with 202 melanocytic lesions, corresponding to 76 melanomas, 114 nevi, and 12 Spitz or Reed nevi. MAIN OUTCOME MEASURES Correlation of dermoscopic patterns in melanocytic lesions with confocal microscopic findings and conventional histopathologic findings. RESULTS Characteristic architectural and cytologic substrates were identified in vivo with the use of confocal microscopy and correlated with histopathologic features. Pigment network atypia was evidenced through confocal microscopy as a disarrangement of dermoepidermal junction architecture and cellular atypia. Pigmented globules consisted of cell clusters, corresponding to melanocytic nests identified on histopathologic analysis. Black dots correlated with intraepidermal reflective spots or with large pagetoid cells in nevi and melanoma, respectively. Blue structures usually consisted of numerous pleomorphic cells, corresponding to malignant melanocytes and inflammatory cells in melanomas, whereas plump bright cells, corresponding to melanophages on histopathologic analysis, characterized benign lesions. Within regression, a retiform distribution of collagen fibers, which sometimes intermingled with melanophages and rarely with nucleated cells, was observable. CONCLUSIONS The knowledge of the cytologic and architectural aspects of the different dermoscopic patterns, as they appear by in vivo confocal microscopy, may guide the user to the identification of specific substrates in melanocytic lesions and consequently the interpretation of the dermoscopic features.

Development of a two-step method for the diagnosis of melanoma by reflectance confocal microscopy

BACKGROUND Reflectance confocal microscopy (RCM) has been shown to improve accuracy in the differentiation of nevus from melanoma, but only a few studies have evaluated both melanocytic lesions (ML) and non-ML. OBJECTIVE We sought to develop an algorithm for the in vivo diagnosis of skin tumors by RCM. METHODS In 143 patients we evaluated 154 skin tumors (100 melanocytic, 54 nonmelanocytic) by RCM before their excision. We analyzed RCM features on stored images and performed univariate and multivariate analyses to determine the association of RCM features with tumor types. RESULTS Four confocal features differentiated ML from non-ML: cobblestone pattern of epidermal layers, pagetoid spread, mesh appearance of the dermoepidermal junction, and the presence of dermal nests. Within ML, the presence of roundish suprabasal cells and atypical nucleated cells in the dermis was associated with melanoma, and the presence of edged papillae and typical basal cells was associated with nevi. Based on the correlation of RCM features with dermatoscopy and histology, we developed a two-step algorithm for the diagnosis of skin tumors by RCM. LIMITATIONS This is a preliminary study, and the results must be validated in further studies with a larger number of cases. CONCLUSION RCM appears to be helpful in improving the presurgical diagnosis of difficult skin tumors.

TERT Promoter Mutation Status as an Independent Prognostic Factor in Cutaneous Melanoma

BACKGROUND Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. METHODS 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. RESULTS TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). CONCLUSIONS UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.

Association of MC1R Variants and Host Phenotypes With Melanoma Risk in CDKN2A Mutation Carriers: A GenoMEL Study

Background Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. Methods We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. Results Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02). Conclusion Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

Impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions

The number needed to treat (NNT) ratio is an effective method for measuring accuracy in melanoma detection. Dermoscopy reduces the number of false positives and subsequently unnecessary excisions. In vivo reflectance confocal microscopy (RCM) is a noninvasive technique that allows examination of the skin with cellular resolution.

Association between sleep disordered breathing and aggressiveness markers of malignant cutaneous melanoma

Some recent studies have shown an association between sleep disordered breathing (SDB) and cancer mortality and incidence but no study has focused on a specific type of cancer. The objective of this study was to analyse the relationship between the severity of SDB and factors related to cutaneous malignant melanoma (CMM) aggressiveness. We performed a multicentre observational study in 82 consecutive patients diagnosed with CMM. 56 patients in whom melanoma measurements were available were finally included in the study. Melanoma measurements of aggressiveness included: tumour mitotic rate, Breslow index, presence of ulceration, stage of disease and growth rate of melanoma. A sleep study was performed in all the included patients. Multivariate analyses were used to examine the independent relationship between SDB severity (apnoea–hypopnea index (AHI) and nocturnal oxygen desaturation indexes (ODI3% and ODI4%)) and measures of CMM aggressiveness. 60.7% of patients had SDB (AHI ≥5) and 14.3% severe obstructive sleep apnoea (AHI ≥30). In fully adjusted multivariate analyses, AHI (OR 1.08, 95% CI 1.02–1.14), ODI3% (OR 1.08, 95% CI 1.02–1.11) and ODI4% (OR 1.1, 95% CI 1.02–1.2) were independently associated with an increased melanoma growth rate. Furthermore, AHI, ODI4% and ODI3% were significantly correlated with other aggressiveness factors of CMM, such as Breslow index, presence of ulceration and mitotic index. SDB severity markers are associated with some aggressiveness markers of CMM. This study adds evidence on the relationship between sleep disordered breathing and cancer aggressiveness http://ow.ly/tMRYu

Non-invasive management of non-melanoma skin cancer in patients with cancer predisposition genodermatosis: a role for confocal microscopy and photodynamic therapy

Background  Patients with genodermatosis such as Gorlin syndrome (GS) and Xeroderma pigmentosum (XP) require a close follow‐up for early diagnosis and treatment of skin cancer. We aimed to evaluate the efficacy of methyl‐aminolevulinate (MAL) photodynamic therapy (PDT) in basal cell carcinomas (BCCs) from patients with GS and XP, and to determine the utility of reflectance confocal microscopy (RCM) in the diagnosis and the evaluation of therapeutic response.

Melanomas Detected in a Follow-up Program Compared With Melanomas Referred to a Melanoma Unit

OBJECTIVE To compare melanomas diagnosed in patients included in follow-up programs with melanomas diagnosed in patients referred to a melanoma unit. DESIGN Retrospective analysis of 215 consecutive melanomas diagnosed between 2007 and 2008. SETTING Melanoma Unit, Hospital Clinic of Barcelona, Barcelona, Spain. PATIENTS The study included 201 patients (105 men and 96 women), 40 of whom were included in a follow-up program in our unit and 161 of whom were referred for evaluation. MAIN OUTCOME MEASURES Clinical (ABCD algorithm), dermoscopic (ABCD rule of dermoscopy), and main histologic characteristics were evaluated in both groups. RESULTS Most melanomas diagnosed in follow-up did not fulfill some of the ABCD criteria, and only 12.0% fulfilled all 4 ABCD criteria, in contrast with 63.6% of the melanomas referred for evaluation (P < .001). The total dermoscopy score was lower in melanomas diagnosed in follow-up (5.04 vs. 6.39, P < .01), and 36% were misclassified as benign in this group according to the total dermoscopy score. Seventy percent of melanomas diagnosed in follow-up were in situ; among invasive melanomas, the Breslow index was significantly lower in the group of melanomas diagnosed in follow-up, with a mean (range) of 0.55 (0.25-0.90) mm vs 1.72 (0.25-13.00) mm (P < .001). CONCLUSIONS The inclusion of patients who are at high risk for melanoma in follow-up programs allows the detection of melanomas in early stages, with good prognosis, even in the absence of clinical and dermoscopic features of melanoma. In the general population without specific surveillance, melanoma continues to be diagnosed at more advanced stages.